Andrzej Jakubowiak, MD, discusses the impact of a recent cross-study comparison analysis and the continued role of autologous stem cell transplantation in treatment of patients with multiple myeloma.
Andrzej Jakubowiak, MD, PhD
Autologous stem cell transplantation (ASCT) further improves outcomes when added to the triplet regimen of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) compared with KRd alone for patients with newly diagnosed multiple myeloma, according to results of a recent cross-study comparison analysis.
The analysis compared a phase I/II trial of patients with newly diagnosed multiple myeloma who received extended treatment with KRd with similar patients who received KRd plus ASCT in a subsequent ongoing phase II trial. At the end of 8 cycles, the stringent complete response (sCR) rate was 72% for patients who received KRd plus ASCT (n = 50) compared with 30% for patients who received KRd without ASCT (n = 44). sCR was 88% (n = 26) for those who received KRd plus ASCT (n = 26) compared with 51% for those received KRd alone (n = 41) at the end of cycle 18.1
At a median follow-up of 17.8 months, the 2-year progression-free survival (PFS) rate was 99% for KRd plus ASCT group compared with 92% for the KRd-alone group at median follow-up of 47.5 months.
The types and rates of adverse events (AEs) pre- and post-ASCT in the 2 groups were comparable.
OncLive: What were the most significant findings from this analysis?
To better understand the impact of this analysis and the continued role of ASCT in treatment of patients with multiple myeloma, OncLive spoke with Andrzej Jakubowiak, MD, PhD, lead author on the analysis and professor of Medicine and director of the Myeloma Program of the University of Chicago School of Medicine.Jakubowiak: The direct conclusion of this analysis was that even in the context of an effective and powerful regimen like KRd, transplant adds additional value and improves efficacy, which we measured by surrogate endpoints. For example, at the end of the total 8 cycles in both studies, sCR rate was 30% without transplant and with transplant it was 72%. That even improves further down the road. The transplant is still valid, even in the context of most effective regimens.
Our results are also very mature and updated now from the original phase I/II study and what we see is close to amazing. What we conclude with this cross-study comparison is probably the best results we’ve seen with multiple myeloma. After a 4-year follow-up, PFS was 69% in the original study for patients treated with KRd for extended treatment without transplant. That 4-year progression in the current study was too early to measure but at 2-year follow-up, the curve with transplant clearly tracks up. We predict it will be even better than without transplant. It will not only be a high rate of stringent responses, but potentially a high rate of PFS.
There are a couple other important points from these studies. In both studies, there were high minimal residual disease (MRD)-negative rates. In the earlier study, we did not have as robust of an evaluation of MRD among residual disease.
What impact will these findings have?
However, in the current study, we do it more systemically at landmark time points. I specifically show results at the end of cycles 8 and 18, and those MRD results are close to amazing because we see rates of MRD by current IMWG criteria, which means that MRD is counted only in patients with complete or stringent complete response—exceeding 70% at those respective time points. We believe these are truly good numbers, which will be validated as soon as the study is completed.What this means in regards to where the field is going is, number one, the results are likely as good as they are because we are achieving such a high rate of MRD-negative disease. I would like to dare to say that we are even eliminating this disease for good for some of these patients.
Secondly, this is something we could potentially think about using as a predictor of outcome at the earlier time point. With those 2 studies, as well as other previous studies, there is some comparative predictability of people achieving some level of response.
What questions remain regarding this research?
We believe that because of these results with KRd treatment, we can use KRd with or without transplant as the backbone of future studies. As we showed in principal, transplant adds on to KRd. Something else could be added, such as monoclonal antibodies—which I know many of us are planning to do.There are critical questions to address at this point. Some patients who had good response may not need any more treatment if they have with MRD-negative disease, sCR, and lack of evidence relapse for long period of time. It is too early to make these decisions, but we can potentially start identifying patients who can stop treatment early or maybe design a study that will help define the proper duration of therapy for these patients. It is not going to be 6 cycles— it will probably more than that—but it doesn’t need to be 2 or 3 years. The majority of patients may not need treatment for years to come and some of them might be cured.
We need some other points of information for our decision-making. MRD may not be good enough; we need to be better at identifying patients who are at higher risk of relapsing despite achieving good responses.
Another remaining question we need to answer is, “How do we identify patients with myeloma into subgroups?” We have done this for a long time with cytogenetics, but anyone who has done this for a long time will also tell you that all the cytogenetic fluorescence in situ hybridization (FISH) studies are so imperfect at identifying those subgroups of patients.
Because of that, it is difficult to convince ourselves that if we would like to do a study in high-risk patients, for example, that this is the way to go. However, what are the alternatives? We have known about gene expression profiling as an option for narrowing those groups to more definite subgroups of myeloma, and that is something that has been widely discussed at meetings.
Jakubowiak A, Raje N, Vij R. Improved efficacy after incorporating autologous stem cell transplant (ASCT) into Krd treatment with carfilzomib (Cfz), lenalidomide (Len), and dexamethasone (Dex) in newly diagnosed multiple myeloma. Presented at: 2016 European Hematology Association Congress; June 9-12, 2016; Copenhagen, Denmark. Abstract S101.